Monday, March 30, 2015

Antibiotic resistance

Ken and I just saw Michael Grazione's excellent, sobering film, Resistance, about the looming loss of antibiotics in the medicinal arsenal.  Bacteria that can make us very ill, and even kill us, are quickly, and unavoidably developing resistance to the chemicals that control them.  As Meryn McKenna writes in her excellent, also sobering piece, "Imaging the Post-Antibiotic Era", a world without antibiotics is going to look a lot like 1935; simple infections will become fatal once again, routine surgery, and cancer treatments that require repressing the immune system, and so on will no longer be possible. (McKenna is a journalist specializing in public health issues; her work is always worth reading, and she has a major role in the film.)

There are several very serious problems here, as we stare into the maw of the post-antibiotic era: despite the fact that the problem is widespread and growing, antibiotics are still being widely, and wantonly misused.  And, economic and political interests are standing in the way of changing this.

Penicillin, of course, was the first antibiotic discovered, in the 1930's.  Even before it was being widely used, bacteria were developing resistance.  Indeed, all antibiotics quickly lose their effectiveness, as the discoverer of penicillin, Alexander Fleming, warned in the 1940's, because they are a potent artificial selective force for resistance.  That's why they should be used only when necessary.

Year of first use and then clinical resistance for each antibiotic; Nature Chemical Biology, 2007; Clatworthy et al.

Antibiotics are like any other environmental agent when it comes to the evolutionary dynamics of any species, including bacteria.  If gene variants are present in the bacterial population that allow a subset of bugs to survive the chemical onslaught, this leads to resistance.  Antibiotics and chemotherapy against tumor cells are similar in this regard -- generally not strong enough to wipe out the entire population of cells.  When protective mutations are present, the overall population diminishes initially, as the majority of susceptible individuals are killed off, which leaves the field to the resistant few, which then proliferates, rendering therapy that was previously beneficial to the patient useless.

The situation is usually not quick or simple, but this is the simple nature of evolutionary adaptation.  Molecular attacks on cells can in principle act as selective factors that lead to resistance to the attack. There is no perfect or permanent solution, unless there is a mode of attack so fundamental to the target cells that they simply cannot evade it by modifying their own molecular makeup.  Such modes would be very desirable, but are not generally part of the arsenal we have against microbes or cancer cells and the like.

Instead, intervention approaches need to be used cleverly and sparingly so that resistance mutations don't have any advantage in the organism's population.  Indeed, since these organisms like bacteria (or your normal body cells) are the produce of eons of adaptation, most changes will be at least slightly harmful if they do anything, and will be outcompeted into oblivion by the 'normal' competitors in the population.  The problem is that this basic evolutionary truth is too often neglected. The reasons are only human, about short-sightedness, unawareness, personal vested interests, and so on.

There are several ways in which antibiotics are over-used that apparently lead to the present state of the problem.  Doctors and patients both are part of the problem; patients demanding treatment, even for viral infections, and doctors prescribing antibiotics just in case the infection is actually bacterial.    Of course, a big villain in the piece, discussed at length in Resistance, is routine use of antibiotics in animal agriculture, to promote growth in their densely raised livestock.  These are well-documented ways in which too much use leads to natural selection of resistant strains.

As the film also notes, there are widely known financial reasons for under-development of antibiotics by pharmaceutical firms.  There are also many technical limits, such as that many pathogens have not been growable and hence testable in the lab.  Clever ways around these problems probably exist--but we must make the research fundable.

There is no current known way to avoid the development of antibiotic resistance.  But, eliminating its use as a growth promoter in livestock would slow down the speed at which new drugs become useless, culturing infected tissues in real time in the doctor's office so that only bacterial infections are treated with antibiotics would help, patients using them for the proper length of time would help, and so on.

More research into drugs that are less likely to spawn resistance would help enormously as well.  And, subsidies for drug companies who do choose to invest in what is not a highly profitable class of drugs.  We need somehow to decouple research from profits so that this research will be done.  But this requires recognition of the enormity of the problem and its potentially catastrophic consequences.  If we take that seriously, we would divert huge amounts of funds in this research direction.

Infectious diseases and their potential future pandemic effects are far more important to study than many of the things we are currently pouring money into.  Of course, we think that much of research on enumerating individually trivial genetic variants related to late-onset, mainly environmentally caused diseases (the goal of the proposed 'precision' medicine) is hugely wasteful.

Indeed, many who do genomic research that leads hardly anywhere have the gear and technical skills to take the antibiotic issues on with much more potential for real health gains.  There's no sense in knowing a person's minor genetic risks factors for, say, adult-onset diabetes, if they're going to be eaten alive by bacteria first.  That's research emperors fiddling while Rome burns.


James Goetz said...

"More research into drugs that are less likely to spawn resistance would help enormously as well."

Hi Anne, I don't know how science can predict this. We might be able to avoid predictable new bacterial phenotypes, but a new bacterial phenotype with an unpredictable resistance could always be around the corner, as far as I know. Peace, Jim

Anne Buchanan said...

Jim, the idea is that some parts of bacterial DNA are freer to vary than others. That is, they are freer to mutate to resist the antibiotic coming at it, and these are generally what confers antibacterial resistance. So, a drug that would target a function of the bacteria that is less prone to mutation because it's crucial to the survival of the bug would be better than something that targets the 'resistome' the genes that confer resistance and are freer to mutate. Or, at least that's my understanding.

That wouldn't guarantee that the bug wouldn't become resistant, because it probably would. Just, along with more judicious use of new antibiotics, might slow it down.

Anne Buchanan said...

And then there is this: a 1000 year old recipe for a salve made of onion, garlic and part of a cow stomach kills MRSA.

James Goetz said...

My policy is to avoid rubbing garlic into my eyes, but I consider exceptions to every rule....

Unknown said...

I agree with James. More research and discussions on the topics helps us to know more about the topic. So I am planning to attend a Antibiotic event (